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Cyclin dependent kinase 1-dependent activation of APC/C ubiquitin ligase

Fujimitsu, K; Grimaldi, M; Yamano, H; (2016) Cyclin dependent kinase 1-dependent activation of APC/C ubiquitin ligase. Science , 352 (6289) pp. 1121-1124. 10.1126/science.aad3925. Green open access

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Abstract

Error-free genome duplication and segregation are ensured through the timely activation of ubiquitylation enzymes. The anaphase-promoting complex/cyclosome (APC/C), a multisubunit E3 ubiquitin ligase, is regulated by phosphorylation. However the mechanism remains elusive. Using systematic reconstitution and analysis of vertebrate APC/Cs under physiological conditions, we show how cyclin-dependent kinase 1 (CDK1) activates the APC/C through coordinated phosphorylation between Apc3 and Apc1. Phosphorylation of the loop domains by p9/Cks2 (CDK regulatory subunit)-CDK1 controlled loading of coactivator Cdc20 onto APC/C. A phosphomimetic mutation introduced into Apc1 allowed Cdc20 to increase APC/C activity in interphase. These results define a previously unrecognised subunit-subunit communication over a distance and the functional consequences of CDK phosphorylation. Cdc20 is a potential therapeutic target and our findings may facilitate the development of specific inhibitors.

Type: Article
Title: Cyclin dependent kinase 1-dependent activation of APC/C ubiquitin ligase
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/science.aad3925
Publisher version: http://dx.doi.org/10.1126/science.aad3925
Language: English
Additional information: Copyright © 2016 American Association for the Advancement of Science. All rights Reserved. This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Journal (27 May 2016: vol. 352, issue 6289, pp. 1121-1124; DOI: 10.1126/science.aad3925).
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: http://discovery.ucl.ac.uk/id/eprint/1489820
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